The temperature dependence of binding entropy is a selective pressure in protein evolution
Bibliographic record
Abstract
Abstract Proteins operate through ligand and solvent interactions governed by thermodynamics, yet the enthalpy-entropy trade-offs that guide their functional evolution remain poorly understood. The LacI/GalR family (LGF) of transcription factors provides a system for examining how these trade-offs evolve over billions of years but has seldom been studied from a full thermodynamic perspective. While the evolution of ligand specificity has been well-studied, the thermodynamic determinants underlying the changes in specificity is not well understood – especially how proteins alter thermodynamic strategies to optimize affinity. By reconstructing LGF ancestors, we reveal a shift from entropy-driven binding in the most distant ancestor, to enthalpy-driven binding in the most recent ancestor and extant LacI. The most distant ancestor is characterized by the ability to bind its ligand in an open and dynamic conformation, and we propose that entropically-driven binding is driven by the presence of entropic reservoirs. This thermodynamic binding trade-off between the most distant and most recent ancestor is in accordance with the concept of ancient life that existed in a hot Earth environment, where higher temperatures enhanced entropically-driven binding. This suggests that molecular binding mechanisms evolved not just for ligand specificity, but to adapt to environmental pressures such as cooling Earth temperatures where enthalpic binding modes are favored.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".